原创 一篇nature 文章，科技的进步，介绍热门话题：猪到人的移植向现实迈出了一大步

Nature Medicine volume 28, page423 (2022)>Cite this article

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The use of transgenic pigs as a source of organs and tissues for patients in need could revolutionize medicine — but to achieve that goal, data from clinical trials and forthright assessment of the ethics of animal-to-human transplants will be critical.

The shortage of donated organs for transplantation is dire. In the United States alone, more than 100,000 people are on waiting lists for organ and tissue transplants, and 17 people die each day while waiting. Xenotransplantation — the process of transplanting organs or tissues between different species — with its promise of providing a virtually unlimited supply of organs, has been pursued for decades with little success. But over the past 6 months, a series of stunning reports has provided the first results showing the feasibility of transplanting organs from transgenic pigs into humans.

On 25 September of last year and then again on 22 November, Robert Montgomery of NYU Langone’s Transplant Institute transplanted a pig kidney into a recently deceased recipient maintained on a ventilator. Over the course of the following few days, the transplanted kidneys survived immunological rejection and maintained their function, producing urine and clearing creatinine from the blood. A second team, led by Jayme Locke at the University of Alabama at Birmingham, reported similar results in another recently deceased recipient. Then, on 7 January of this year, Bartley Griffith and Muhammad M. Mohiuddin, of the University of Maryland Medical Center, transplanted a heart from a transgenic pig into a living person who had terminal heart failure and was too sick to qualify for a human heart transplant or a mechanical assist device. The heart was not initially rejected, and the patient was reported to be doing well after surgery but died 2 months later for unclear reasons.

These clinical studies, marking a watershed moment for the field of xenotransplantation, have been enabled by a series of technological breakthroughs. Researchers have zeroed in on a set of three pig genes, encoding enzymes that make sugars recognized as foreign antigens, that need to be deleted to avoid acute immunological rejection of the transplanted organ. Transgenic pigs have been engineered to express a set of approximately ten human genes with the goal of preventing long-term organ rejection and preserving organ function, including genes encoding molecules that block the complement arm of the immune response, dampen systemic inflammation and reduce the risk of coagulation. Strides have also been made in improving the immunosuppressive regimens given to transplant recipients. These advances have culminated in preclinical studies, using pig–to–nonhuman primate models, in which pig kidneys have been able to support life for more than 1 year, and pig hearts have been able to do so for more than 6 months.

A potential concern about the safety of xenotransplantation is the presence of a large number of porcine endogenous retroviruses in the pig genome. These retroviruses, known as ‘PERVs’, could theoretically jump into other tissues in the recipient and lead to tumorigenesis or immunodeficiency. Although transmission of PERVs has not been seen in people with diabetes given transplantation of pig pancreas cells, the safety risk of PERVs is still far from clear, and PERV-free pigs suitable for use in xenotransplantation have recently been generated by CRISPR technology.

The time is now ripe to put the safety and efficacy of xenotransplantation to the test in clinical trials, studying immune responses to the transplanted organ, the ability of the organ to function, and the survival and quality of life of recipients. Initially, transplantation of pig kidneys may be the most feasible, as in the case of organ failure or adverse events, the transplanted kidney can be removed and the patient can be given rescue therapy with dialysis.

Given the large number of people who are waiting for a donor organ, the question of equitable access to trial participation may be a thorny one. Should patients most likely to die before receiving a human organ have priority to enroll in a trial? What other types of eligibility criteria should be considered, such as the overall health of the patient or evidence of immunological reactivity against pig antigens?

Such trials will also need to take into account the risk of transmission of PERVs or other viruses, with long-term follow up to monitor the potential for transmission of infectious diseases. Indeed, the US Public Health Service has called for lifelong surveillance to assess the public health risk from zoonotic infectious disease following xenotransplantation.

Concerns about animal welfare also need to be taken into consideration. Although the use of transgenic pigs does not present the same types of ethical concerns that would arise from the creation of pig–human chimeras, which have also been proposed as a source of organs for xenotransplantation, large-scale farming of pigs under the strictly hygienic conditions required does raise novel ethical concerns. Ultimately, patients, healthcare workers and the overall public will need to support the concept of using pig organs as a life-saving intervention.

The recent groundbreaking clinical results showing the feasibility of transplanting transgenic pig organs into humans raise hopes that xenotransplantation can help solve the critical shortage of human donor organs. The challenge now is in taking the next steps for demonstrating efficacy and safety in clinical trials and making xenotransplantation an everyday reality for patients in need of transplants.

猪到人的移植向现实迈出了一大步

使用转基因猪作为有需要的病人器官和组织的来源可能会彻底改变医学——但是为了实现这一目标，来自临床试验的数据和对动物到人类移植的伦理道德的直接评估将是至关重要的。

用于移植的捐赠器官的短缺是可怕的。仅在美国，就有超过10万人在等待器官和组织移植，每天都有17人在等待中死亡。异种移植——在不同物种之间移植器官或组织的过程——承诺提供几乎无限的器官供应，但几十年来却鲜有成功。但是在过去的6个月里，一系列令人震惊的报告提供了初步结果，表明转基因猪的器官移植到人体内是可行的。

去年9月25日和11月22日，纽约大学朗格尼移植研究所的罗伯特·蒙哥马利(Robert Montgomery)分别将猪肾移植到一名靠呼吸机维持的近期死亡的患者体内。在接下来的几天里，移植的肾脏经受住了免疫排斥，并保持了自身的功能，能够产生尿液并清除血液中的肌酐。由伯明翰阿拉巴马大学(University of Alabama at Birmingham)的杰米·洛克(Jayme Locke)领导的第二个研究小组，在另一个最近去世的患者身上报告了类似的结果。今年1月7日,Bartley格里菲斯和穆罕默德·m·Mohiuddin马里兰大学的医疗中心,将转基因猪的心脏移植到一个活生生的人终端心脏衰竭和太恶心,符合人类心脏移植或机械辅助设备。心脏最初没有排斥反应，据报道患者术后恢复良好，但2个月后死亡，原因不明。

这些临床研究，标志着异种移植领域的一个分水岭，已经实现了一系列的技术突破。研究人员已经将注意力集中在猪的一组三个基因上，这些基因编码的酶使糖被识别为外来抗原，需要删除这些抗原以避免移植器官的急性免疫排斥反应。转基因猪已经被设计成表达一组大约10个人类基因，目的是防止长期的器官排斥和保持器官功能，包括基因编码分子，阻断免疫反应的补体臂，抑制全身炎症和减少凝血风险。在改善移植受者的免疫抑制方案方面也取得了进展。这些进展在临床前研究中达到了顶峰，使用猪到非人的灵长类模型，猪的肾脏已经能够支持生命超过1年，猪的心脏已经能够支持生命超过6个月。

异种移植安全性的一个潜在问题是猪基因组中存在大量的猪内源性逆转录病毒。这些逆转录病毒被称为“perv”，理论上可以进入受体的其他组织，导致肿瘤发生或免疫缺陷。虽然在接受猪胰腺细胞移植的糖尿病患者中尚未发现perv的传播，但perv的安全风险仍远未明确，而且最近通过CRISPR技术已经产生了适合用于异种移植的无perv猪。

将异种移植的安全性和有效性用于临床试验的时机已经成熟，研究移植器官的免疫反应、器官的功能能力以及受者的生存和生活质量。最初，猪肾移植可能是最可行的，因为在出现器官衰竭或不良事件的情况下，移植的肾可以被摘除，患者可以接受透析的抢救治疗。

考虑到等待器官捐赠的人数众多，公平参与试验的机会可能是一个棘手的问题。那些在接受人体器官移植前最有可能死亡的患者是否应该优先参加试验?还应考虑哪些其他类型的资格标准，如患者的整体健康状况或对猪抗原的免疫反应性证据?

这类试验还需要考虑到perv或其他病毒传播的风险，并进行长期跟踪，以监测传染病传播的可能性。事实上，美国公共卫生服务部门已经呼吁终身监测，以评估异种移植后人畜共患传染病的公共卫生风险。

对动物福利的关注也需要被考虑进去。尽管转基因猪的使用不存在相同类型的伦理问题,源于创造猪-人嵌合体,这也被提议作为异种移植的器官来源,大规模种植所需的猪在严格的卫生条件下提高伦理问题。最终，患者、医护人员和整个公众都需要支持使用猪器官作为救命干预的概念。

最近突破性的临床结果表明，将转基因猪器官移植到人体内是可行的，这为异种移植解决人类捐献器官严重短缺带来了希望。目前的挑战是采取下一步措施，在临床试验中证明异种移植的有效性和安全性，并使需要移植的患者每天都能接受异种移植。